Prophylaxis Regimens for Pneumocystis jirovecii Pneumonia in Non-HIV, Non-Malignant Immunocompromised Adults: A Systematic Review and Network Meta-Analysis.

Pneumocystis jirovecii pneumonia (PCP) prophylaxis is established in people with human immunodeficiency virus (HIV), but guidance for non-HIV, non-malignant immunocompromised adults remains fragmented. We searched eight databases and registries through 18 May 2026 (PROSPERO CRD420261396046). Because the evidence did not support a clinically exchangeable network, we evaluated four linked routes: comparative effectiveness, active-regimen safety, trimethoprim-sulfamethoxazole (TMP-SMX) discontinuation burden, and descriptive second-line evidence. Fifty-four full-length peer-reviewed reports were included. The primary effectiveness synthesis comprised 27 studies, 34,473 participants, and 243 PCP events. Compared with no prophylaxis, standard-dose TMP-SMX (odds ratio [OR] 0.30, 95% confidence interval [CI] 0.18-0.48; low certainty) and low-dose TMP-SMX (OR 0.08, 95% CI 0.03-0.18; low certainty) were associated with lower PCP incidence. Lower-intensity TMP-SMX strategies were associated with fewer treatment-limiting discontinuations than standard/conventional-dose TMP-SMX (OR 0.234, 95% CI 0.145-0.377). Across 33 TMP-SMX studies/cohorts, the pooled discontinuation proportion was 12.3% (95% CI 9.4-15.9%). Breakthrough PCP occurred in 0.5% of 1056 second-line recipients. TMP-SMX had the clearest protective association; however, low-dose evidence did not establish superiority or non-inferiority, and second-line data did not permit comparative estimates or regimen ranking.